The subject of the present invention is new human NK3 receptor selective antagonist compounds for the preparation of medicaments useful in the treatment of psychiatric illnesses, illnesses of psychosomatic origin, hypertension and, in general terms, any central or peripheral pathology in which neurokinin B and the NK3 receptors play a role in interneuronal regulation, a process for obtaining them and pharmaceutical compositions containing them as an active principle.
An illness of psychosomatic origin denotes illnesses with their origin in the central nervous system and their peripheral pathological effects.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK1, NK2 and NK3. Substance P (SP) is the endogenous ligand of NK1 receptors, neurokinin A (NKA) that of NK2 receptors and neurokinin B (NKB) that of NK3 receptors.
NK1, NK2 and NK3 receptors have been found in various species. For example, NK3 receptors have been identified in guinea pigs, rats and monkeys (Br. J. Pharmacol., 1990, 99, 767-773; Neurochem. Int., 1991, 18, 149-165); they have also been identified in man (FEBS Letters, 1992, 299 (1), 90-95).
A review by C. A. Maggi et al. investigates tachykinin receptors and their antagonists and describe pharmacological studies and applications to human therapy (J. Autonomic Pharmacol., 1993, 13, 23-93).
Patent Application EP-A-0 673 928 describes a family of human NK3 receptor antagonist compounds with the formula: 
in which R1, RII, and R2 have different values.
More particularly, a selective antagonist, (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl) piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, has been described (EP-A-0673 928; Peptides and their antagonists in tissue injury, Montreal, Canada, Jul. 31-Aug. 3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0.9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, Apr. 6-8, 1995; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur. Congress Pharmacol., Milan, Jun. 16-19, 1995).
The subject of Patent Application WO 97/10 211 is compounds with the formula: 
in which B, R1xe2x80x2, R2xe2x80x2 and Ar1 take different values. These compounds are described as having a very high affinity for human NK3 receptors.
Non-peptide compounds have now been found which have a very high affinity for human NK3 receptors and marked specificity for the aforesaid receptors plus good bioavailability when administered orally.
Moreover, compounds in accordance with the present invention have good pharmacological activity in animals, decidedly superior to that of (+)-N-[1-[3-[l-benzoyl-3-(3,4-dichlorophenyl) piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide.
These compounds can be used for the preparation of medicaments useful in the treatment of psychiatric illnesses or those of psychosomatic origin and all central or peripheral illnesses in which neurokinin B and the NK3 receptor play a role in interneuronal controls.
By very high affinity for human NK3 receptors, we mean an affinity characterized by an inhibition constant Ki which is generally less than 5xc3x9710xe2x88x929 M.
In ligand fixation studies, the Ki inhibition constant is defined by the Cheng-Prusoff ratio (in Receptor Binding in Drug Research, eds. R. A. O""BRIEN. Marcel Dekker, New York, 1986):   Ki  =            IC      50              1      +                        [          L          ]                Kd            
[L]: concentration of the ligand,
Kd: dissociation constant of the ligand,
IC50: concentration which inhibits 50% of ligand fixation.
By marked specificity for human NK3 receptors, we mean that the inhibition constant (Ki) for human NK3 receptors is generally at least 100 times lower than the inhibition constant (Ki) for NK2 receptors or for NK1 receptors of different species.
The subject of the present invention is compounds with the formula: 
in which:
R1 and R2 each represent, independently of one another, hydrogen or a (C1-C3) alkyl;
or R1 and R2 together with the nitrogen atom to which they are bound constitute a heterocyclic radical chosen from among: a pyrrolidin-1-yl, a piperidin-1-yl, a morpholin-4-yl
or R1 represents a methyl and R2 represents a methoxy;
R3 represents hydrogen or a (C1-C3) alkyl; as well as their salts with mineral or organic acids and their solvates.
Formula (I) compounds, in accordance with the invention, consist of both optically pure isomers and racemic compounds.
Salts of formula (I) compounds can be formed. These salts include both those with mineral or organic acids, which enable a suitable separation or crystallisation of formula (I) compounds, such as picric acid or oxalic acid or an optically active acid, for example a mandelic or camphosulphonic acid, and those which form pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, sulphate, hydrogensulphate, dihydrogenphosphate, methanesulphonate, maleate, fumarate, succinate, naphthalene-2-sulphonate, glyconate, gluconate, citrate, isethionate, benzenesulphonate, paratoluenesulphonate, benzoate. Pharmaceutically acceptable salts are preferred.
In accordance with the present invention, formula (I) compounds are preferred in which R1 and R2 each independently represent hydrogen or a (C1-C3)alkyl. More particularly, compounds are preferred in which R1 and R2 each independently represent hydrogen or a methyl. Formula (I) compounds in which R3 is hydrogen are preferred in particular.
In accordance with the present invention, optically pure compounds of formula (I) are preferred and very particularly (+) isomers with an (R) configuration.
Thus, in accordance with one of its aspects, the present invention concerns in particular 1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(Nxe2x80x2,Nxe2x80x2-dimethylureido)-4-phenyl-piperidin-1-yl]propyllpiperidine, as well as its salts and solvates. The (+) isomer of this compound being particularly preferred.
1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(Nxe2x80x2-methylureido)-4-phenylpiperidin-1-yl]propyl]piperidine and 1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-ureido)-4-phenylpiperidin-1-yl]propyl]piperidine are also preferred, the aforesaid compounds in the form of (+) isomer being particularly preferred.
The subject of the present invention is also a process for the preparation of a formula (I) compound, of its salts and its solvates. This process is characterized in that:
a1) a compound with the formula: 
in which G represents a methyl, phenyl, tolyl or trifluoromethyl group is treated with a piperidine derivative with the formula: 
in which R4 represents an NR3CONR1R2 group or a COOH group, R1, R2 and R3 being as defined above for (I);
b1) when R4=COOH the compound thus obtained with the formula: 
is converted to a formula (I) compound. optionally, the compound thus obtained at stage a1) or at stage b1) is converted to one of its salts or solvates.
Stage a1) of the process in accordance with the invention is carried out in an inert solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene, isopropanol or a mixture of these solvents in the presence or absence of a base. When a base is used, this is selected from among organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of base, the reaction is carried out using an excess of the formula (III) compound and possibly in the presence of an alkali metallic iodide such as potassium or sodium iodide. The reaction takes place at a temperature between ambient temperature and 100xc2x0 C.
At stage b1), when compound (III) used in stage a1) of the process contains a carboxyl group COOH, the conversion to a ureido group NHCONR1R2 takes place in a classical manner through the intermediate formation of an isocyanato xe2x80x94Nxe2x80x94Cxe2x95x90O group with which the appropriate amine NHR1R2 is made to react. If need be, the compound obtained is alkylated by a (C1-C3) alkyl halide in order to obtain a compound in accordance with the invention in which R3=(C1-C3) alkyl.
In accordance with a variant of the process:
a2) a compound with the formula: 
in which G is as previously defined and Pr represents a protective group selected from the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group is treated with a piperidine derivative with the formula: 
in which R4 represents an NR3CONR1R2 group or a COOH group;
b2) the protective group Pr of the compound thus obtained with the formula: 
is selectively eliminated;
c2) the compound thus obtained with the formula: 
is treated with a benzoyl halide;
d2) when the group R4=COOH, the compound thus obtained with the formula: 
is converted to a compound with the formula (I).
Optionally, the compound thus obtained in stage c2) or stage d2) is converted to one of its salts or solvates.
At stage b2), deprotection can be undertaken using known professional methods, for example in an acid medium.
According to another variant of the process:
a3) an alcohol with the formula: 
is oxidized;
b3) the aldehyde thus obtained with the formula: 
is treated with a piperdine derivative with the formula: 
in which R4 is as defined above;
c3) when R4=COOH, the compound thus obtained with the formula: 
is converted to a formula (I) compound.
Optionally, the compound thus obtained at stage b3) or stage c3) is converted to one of its salts or solvates.
In accordance with this latter variant of the process, at stage a3), the oxidation reaction is carried out using oxalyl chloride, dimethylsulphoxide and triethylamine for example, in a solvent such as dichloromethane, at a temperature of between xe2x88x9278xc2x0 C. and room temperature. At stage b3), the formula (III) compound is reacted in the presence of an acid such as acetic acid, in an alcohol solvent such as methanol, to form an imine in situ, which is chemically reduced, using sodium cyanoborohydride for example, or catalytically, using hydrogen and a catalyst such as palladium over charcoal or Raney(copyright) nickel.
In accordance with a variant of the process:
a4) a compound with the formula: 
is treated, in the presence of a base, with a (4-phenylpiperidin-4-ylcarbamic acid ester, preferably the tert-butyl ester, with the formula: 
in which Rxe2x80x2=(C1-C6)alkyl;
b4) the compound thus obtained with the formula: 
is deprotected by the action of an acid;
c4) the compound thus obtained with the formula: 
is first treated by a reactive derivative of carbonic acid in the presence or absence of a base, then with an amine with the formula NR1R2, in order to obtain the desired formula (I) compound.
Optionally, the compound obtained is converted to one of its salts or solvates.
In this latter process, it is possible to combine one or more stages. Thus, for example, stages a4) and b4) can be combined in order to directly obtain compound (XI) from compound (II). It is also possible to combine all the stages of the process in accordance with the invention, i.e. not to isolate the intermediate compounds of formula (X) and (XI).
At stage a4), the base used is chosen from among alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or from among alkali metal carbonates or bicarbonates such as potassium carbonate or potassium bicarbonate. Potassium carbonate is preferably used.
At stage b4), in order to carry out deprotection, a strong acid is used such as hydrochloric acid, trifluoroacetic acid or formic acid.
Among the reactive derivatives of carbonic acid, 1,1xe2x80x2-carbonyldiimidazole, phosgene or p-nitrophenyl chloroformate is preferred. 1,1xe2x80x2-Carbonyldiimidazole is particularly preferred and, in this case, the reaction takes place in the absence of base.
When phosgene or p-nitrophenyl chloroformate is used, the reaction is carried out in the presence of an organic base such as N,N-diisopropylethylamine, N-methylmorpholine or, preferably, triethylamine.
Finally, in accordance with another variant, a derivative of 4-phenylpiperidine with the formula: 
is reacted with the formula (II) compound to directly prepare the formula (XI) compound followed by the stage c4) procedure to prepare the formula (I) compound.
Formula (I) compounds are isolated in the form of free bases or salts using classical techniques.
Thus, when the formula (I) compound is obtained in the form of a free base, salification is achieved through treatment with the chosen acid in an organic solvent. The corresponding salt, which is isolated using standard techniques, is obtained by treatment of the free base, dissolved in an ether such as diethyl ether for example, or in an alcohol such as propan-2-ol or in acetone or in dichloromethane or in ethyl acetate, with a solution of the chosen acid in one of these solvents.
Thus, the following are prepared for example: the hydrochloride, the hydrobromide, the sulphate, the hydrogen sulphate, the dihydrogen phosphate, the methanesulphonate, the oxalate, the maleate, the fumarate, the succinate, the glyconate, the gluconate, the citrate, the isethionate, the benzoate, the naphthalene-2-sulphonate, the benzenesulphonate and the paratoluenesulphonate.
At the end of the reaction, the formula (I) compounds can be isolated in the form of one of their salts, for example hydrochloride; in this case, if necessary, the free base can be prepared by neutralisation of the aforesaid salt with a mineral or organic base, such as sodium hydroxide or triethylamine, or with an alkaline carbonate or bicarbonate, such as sodium or potassium carbonate or bicarbonate.
Formula (II), (IV) and (VII) compounds are obtained using known methods, particularly those which are described in Patent Applications EP-A-0 474 561 and EP-A-0 673 928.
Formula (III) and (IX) piperidines are known or prepared in accordance with known methods such as those described in EP-A-673 928 or WO 96/23787.
The resolution of racemic mixtures of formula (I) compounds enables enantiomers to be isolated. It is, however, preferable to carry out the splitting in two of racemic mixtures from an intermediate compound useful for the preparation of a formula (I) compound such as described in Patent Application: EP-A-0 474 561, EP-A-0 512 901, EP-A-0 591 040 and EP-A-0 673 928.
It is particularly preferable to use a formula (II), formula (IV) or formula (VII) compound as a starting material in an optically pure form.
Thus, in accordance with another of its aspects, the subject of the present invention is a stereospecific process for the preparation of a formula (I) compound having the (R) configuration, of its salts and its solvates, characterized in that a compound with the formula: 
in which G is as defined above is used, in the form of the (+) isomer, as the starting material, and the reaction is then continued in accordance with stage b1) or, alternatively, in accordance with stages a4) to c4) as described above.
The subject of the present invention is also another stereospecific process for the preparation of a formula (I) compound with the (R) configuration, of its salts and its solvates, characterized in that an alcohol with the formula: 
in (+) isomeric form is used as the starting material, and the reaction is then continued in accordance with stages a3) to c3) described above.
The subject of the present invention is also a compound with the formula: 
as well as its salts; in racemic form or in optically pure form, as a key intermediate for the preparation of a formula (I) compound.
Formula (I) compounds above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, tritium or carbon-14 for example. Such labelled compounds are useful in research, metabolic or pharmacokinetic studies and in biochemical tests as receptor ligands.
The affinity of formula (I) compounds for tachykinin receptors has been evaluated in vitro by several biochemical tests using radioligands:
1xc2x0) The binding of [125I] BH-SP (P substance labelled with 125 iodine with the aid of the Bolton-Hunter reagent) to NK1 rat cortex receptors, to the ileum of the guinea pig and human lymphoblastic cells (D. G. Payan et al., J. Immunol., 1984, 133, 3260-3265).
2xc2x0) The binding of [1251] His-NKA to NK2 rat duodenum receptors or guinea pig ileum.
3xc2x0) The binding of [121 ] His [MePhe7] NKB to NK3 receptors of the cerebral cortex of the rat, the cerebral cortex of the guinea pig and cerebral cortex of the gerbil as well as to cloned human NK3 receptors expressed by CHO cells (Buell et al., FEBS Letters, 1992, 299, 90-95).
Trials were conducted in accordance with X. Emonds-Alt et al. (Eur. J. Pharmacol, 1993, 250, 403-413).
Compounds in accordance with the invention markedly inhibit the binding of [125I] His [MePHe7] NKB to NK3 cerebral cortex receptors of the guinea pig and gerbil as well as to human cloned NK3 receptors: the inhibition constant Ki is generally less than 5xc3x9710xe2x88x929M. For the same compounds, it has been found that the inhibition constant (Ki) for rat cerebral cortex NK3 receptors is usually greater than 10xe2x88x928 M and that the inhibition constant (Ki) for the rat duodenum NK2 receptor and rat cortex NK1 receptors is generally greater than or equal to 10xe2x88x927 M.
Compounds in accordance with the present invention have also been evaluated in vivo in animal models.
In the gerbil, rotational behaviour is induced with the intrastriatal administration of a specific NK3 receptor agonist: senktide; it has been found that a unilateral application of senktide into the striatum of the gerbil leads to marked contralateral rotations which are inhibited by compounds in accordance with the invention administered either via the peritoneum or orally. In these tests, compounds in accordance with the invention are active at doses varying from 0.1 mg to 30 mg per kg.
This result shows that compounds in accordance with the invention pass through the blood-brain barrier and that they can block, at the level of the central nervous system, actions specific to NK3 receptors. They may thus be used for the treatment of any central NKB-dependent pathology, such as psychiatric disorders, or any pathology mediated centrally by the NK3 receptor, such as psychosomatic disorders.
In guinea pigs, the effect on the bronchitic and cough response induced by citric acid has been studied using the model described by S. Daoui et al., in Am. J. Resp. Crit. Care Med., 1998, 158, 42-48. In this test, the Example 10 compound has shown an activity 10 times greater than that of osanetant.
Compounds of the present invention are usually administered in unit dosage form. The aforesaid dosage units are preferably formulated in pharmaceutical compounds in which the active principle is mixed with a pharmaceutical excipient.
In accordance with another of its aspects, the present invention involves pharmaceutical compositions containing, as the active principle, a formula (I) compound or one of its pharmaceutically acceptable salts and solvates.
Formula (I) compounds and their pharmaceutically acceptable salts can be used at daily doses of 0.01 to 100 mg per kg of mammal body weight for treatment, preferably at daily doses of 0.1 to 50 mg/kg. In humans, the dose can vary preferably from 0.5 to 4,000 mg per day, more especially from 2.5 to 1,000 mg according to the age of the subject requiring treatment or the type of treatment: prophylactic or therapeutic. Even though these dosages are examples of an average situation, there may be particular cases where higher or lower doses may be appropriate, such dosages also belong to the invention. In accordance with usual practice, the appropriate dosage for each patient is established by the physician according to age, body weight and the response of the aforesaid patient.
According to another of its aspects, the present invention concerns the use of formula (I) compounds, or one of their pharmaceutically acceptable salts and solvates for the preparation of medicaments intended for the treatment of any pathology where neurokinin B and human NK3 receptors are involved.
Diseases for the treatment of which the compounds and their pharmaceutically acceptable salts can be used are, for example, central nervous system diseases such as diseases associated with dopaminergic system dysfunction, such as schizophrenia, Parkinson""s disease, diseases associated with noradrenergic and serotoninergic system dysfunction such as anxiety, panic attacks, concentration disorders, mood disorders, particularly depression, as well as all types of epileptic disorders, in particular Grand Mal epilepsy, dementia, neurodegenerative diseases and peripheral illnesses in which the role of the central nervous system and/or peripheral nervous system takes place via neurokinin B acting as a neurotransmitter or neuromodulator such as somatic disorders related to stress, pain, migraine, acute or chronic inflammation, cardiovascular disordersxe2x80x94hypertension in particular, heart failure, and rhythmic disorders, respiratory disorders (asthma, rhinitis, cough, chronic obstructive bronchitis, allergies, hypersensitivity), gastrointestinal system disorders such as oesophageal ulceration, colitis, gastritis, disorders related to stress (stress-related disorders), irritable bowel syndrome (IBS), irritable bowel disease (IBD), acid hypersecretion (acidic secretion), emesis/nausea (following chemotherapy or postoperative, due to travel sickness or vestibular disorders), food allergies, emesis, vomiting, nausea, travel sickness, diarrhoea, urinary tract disorders (incontinence, neurological bladder), immune system disorders (rheumatoid arthritis), and, more generally, any neurokinin B-dependent pathology.
In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermic, local or rectal administration, the active principles can be administered in unit forms of administration, in mixtures with standard pharmaceutical media, to animals and to human beings. The appropriate unit forms of administration consist of oral forms such as tablets, gelatin capsules, powders, granules and solutions or oral suspensions, sublingual and buccal forms of administration, aerosols, topical forms of administration, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.
When a solid composition is prepared in the form of tablets, a wetting agent such as sodium lauryl sulphate can be added to the active principle, micronized or otherwise, and the whole mixed with a pharmaceutical carrier such as silica, gelatine, starch, lactose, magnesium stearate, talc, gum arabic or the like. Tablets can be coated with saccharose, various polymers or other appropriate materials, or treated in such a way that they have a prolonged or delayed activity and can release a predetermined quantity of active principle in a continuous fashion.
A gelatin capsule preparation is obtained by mixing the active principle with a diluent such as glycol or an ester of glycerol and by incorporating the mixture obtained in soft or hard gelatin capsules.
A preparation in the form of syrup or elixir can contain the active principle in combination with a sweetener, preferably calorie-free, methylparaben and propylparaben as an antiseptic, as well as a taste enhancer and an appropriate colouring agent.
Powders or granules dispersible in water can contain the active principle in a mixture with dispersing agents, wetting agents or suspension agents such as polyvinyl-pyrrolidone, likewise with sweeteners or taste correctors.
For rectal administration, suppositories are used, which are prepared with binding agents which dissolve at rectal temperature, such as cocoa butter or polyethylene glycols.
For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used, which contain dispersing agents and/or pharmacologically compatible dissolving agents, for example propylene glycol or butylene glycol.
Thus, in order to prepare an aqueous injectable solution for intravenous use, a co-solvent can be used such as an alcohol, ethanol for example, or a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as Tween(copyright) 80. In order to prepare an oily injectable solution via the intramuscular route, the active principle can be dissolved in a triglyceride or a glycerol ester.
For topical administration, creams, ointments and gels can be used.
For transdermal administration, patches can be used in multilaminated forms or as a reservoir in which the active principle can be in an alcoholic solution.
For administration by inhalation, an aerosol is used, also containing sorbitan trioleate or oleic acid for example as well as trichlorofluoromethane, dichlorofluoro-methane, dichlorotetrafluoroethane or any other biologically compatible propulsion gas; a system containing the active principle alone or in combination with an excipient in the form of a powder can also be used.
The active principle can also be present in the form of a complex with a cyclodextrin, for example xcex1, xcex2, xcex3-cyclodestrin, 2-hydroxypropyl-xcex2-cyclodextrin and methyl-xcex2-cyclodextrin.
The active principle can also be formulated in the form of microcapsules or microspheres, possibly with one or more carriers or additives.
Implants can be used among the slow release forms useful in the case of long-term treatment. These can be prepared in the form of an oily suspension or in the form of microspherical suspension in an isotonic medium.
In each dosage unit, the active principle of formula (I) is present in quantities adjusted to the daily dosages foreseen. In general, each dosage unit is suitably adjusted according to the dosage and the type of administration foreseen, for example tablets, capsules and similar, sachets, ampoules, syrups and similar, drops such that a given dosage unit contains 0.5 to 1,000 mg of active principle, preferably from 2.5 to 250 mg, to be administered one to four times a day.
The aforesaid compositions can also contain other active substances useful for the desired therapy, such as bronchodilators, antitussives, antihistaminics, anti-inflammatories, corticosteroids, anti-emetics, chemotherapy agents.
Thanks to their very high affinity for NK3 human receptors, and their marked selectivity, compounds in accordance with the invention may be used in radiolabelled form as laboratory reagents.
For example, they permit the characterization, identification and the localization of the human NK3 receptor in tissue sections, or of the NK3 receptor in whole animals by means of autoradiography.
Compounds in accordance with the invention also permit the selection or screening of molecules according to their affinity for the human NK3 receptor. This is implemented then by a displacement reaction of the radiolabelled ligand, the subject of the present invention, from its human NK3 receptor.